It has been proposed that cGMP serves as an intracellular signal mediating the physiological actions of hormones, transmitters, and modulators in the nervous system. There are, however, only a few examples of direct evidence in support of this idea. This study investigates the role of cGMP in a neuromuscular preparation, a synaptic tissue that is anatomically simple, relatively homogeneous, and readily available in large quantities. The long-term goal is to understand the role of cGMP in the modulation of neuromuscular physiology and metabolism. Studies will be carried out with exoskeletal muscles from the leg of the lobster. Two hormones (serotonin and octopamine) alter cAMP levels in this preparation. The effects of these hormones on synaptic transmission have been well studied. In addition, a factor has been partially purified from neurosecretory glands in the lobster eyestalk that increases cGMP up to 50-fold in the preparation. This factor appears to be a novel hormone whose physiological effects remain to be determined. The investigation of the role of cGMP in this preparation will involve several different types of experiments. 1) The factor found in eyestalk extracts will be purified by conventional biochemical techniques, and its effects on the physiological properties of the system will be determined. 2) The physiological effects of this factor will be compared to the effects of pharmacological agents known to alter cGMP levels in the preparation (guanylate cyclase activators and inhibitors, phosphodiesterase inhibitors, and phosphodiesterase resistant cyclic nucleotide analogues). 3) Attempts will be made to establish a hormonal role for the factor by demonstrating voltage and Ca2+-dependent release from the eyestalk, and by measuring circulating levels in the blood. The study of hormonal modulation at neuromuscular junctions may have clinical relevance. In vertebrates, both pre- and postsynaptic effects of catecholamines and cyclic nucleotides have been demonstrated in skeletal muscles, and clinical evidence suggests that abnormalities in this modulatory system may be related to neuromuscular disorders. In addition, both cGMP and cAMP appear to mediate the effects of hormones in the cardiovascular system. Thus, a clearer understanding of the role(s) played by cyclic nucleotides in hormonal modulation of muscle function may be helpful in designing therapies for neuromuscular and cardiovascular disorders.